The Dallas Lifespan Brain Study (DLBS) provides one of the most complete pictures of the changes that occur in brain structure and brain function, as well as their consequences for cognition, over the lifespan. The understanding of how healthy brains either maintain cognitive vitality or transition to pathology is the bedrock upon which future cures for neurological diseases will be built. We must study the entire adult lifespan to understand how early changes in brain structure and function signal future cognitive frailty. There are contrasting models of how brain function changes with age to maintain cognition (maintenance model vs. compensation model). We hypothesize that the model that best characterizes an individual is related to age and life experiences. For example, we predict that brain maintenance underlies effective cognitive function in middle-aged adults, whereas maintenance of cognitive function in old age more likely relies on a shift to compensatory brain activity. The DLBS was initially funded in 2006 by a MERIT award to Denise Park, and we have completed two waves of testing spaced four years apart. We now seek funding for Wave 3, which will occur eight years after Wave 1. This third wave is perhaps the most exciting scientifically, as the eight-year measurement period will allow us to isolate both those who are experiencing precipitous cognitive decline as well as older adults who have largely maintained cognitive vitality over eight years. The study employs a variety of neuroimaging tools that provide considerable breadth in the characterization of the brain, including structural, functional, and vascular imaging as well as a detailed cognitive and psychosocial characterization of participants. In addition, the DLBS also incorporates PET scans that measure deposits of beta amyloid and levels of tau in the brain, identifying subjects who may be in a state of preclinical AD. High levels of amyloid and tau neuropathologies are the primary diagnostic criteria for AD at autopsy, but are also commonly found in healthy, cognitively asymptomatic adults, and the DLBS seeks to disentangle this puzzle. The DLBS focuses on five important issues: (a) what neural footprint (maintenance model or compensation model) is associated with 8-year trajectories of cognitive vitality versus cognitive decline; (b) whether high amyloid accumulation in Wave 1 predicts progression at Wave 3, eight years later, to Mild Cognitive Impairment or Alzheimer's Disease; (c) how life experiences and health factors, conceptualized as neural enrichment and neural depletion factors, impact changes in brain function and cognition; (d) whether change in organization of brain networks at different ages predicts cognitive vitality or decline; and (e) whether changes in cerebrovascular health predicts cognitive trajectories. We can use these data to begin to understand the role of neural and contextual factors in explaining, not only who progresses to a pathological brain disorder like AD, but also identify brain patterns that characterize individuals who maintain cognitive function and brain health.